Pediatric Autoimmune and Chronic Benign Neutropenia

Updated: Sep 08, 2017
  • Author: Susumu Inoue, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Overview

Background

The most common type of chronic neutropenia in pediatric patients is chronic benign neutropenia of childhood, ie, neutropenia lasting over 3 months. Chronic benign neutropenia can be regarded as a synonym for autoimmune neutropenia (primary autoimmune neutropenia [AIN]) in children. [1]  Some investigators have also used the term chronic idiopathic neutropenia as a synonym for chronic benign neutropenia.

The most common form of neutropenia in infants and young children is transient neutropenia with or following a viral illness. It resolves itself within 2 weeks. If it lasts longer than that, or the child is very ill, then a full workup for neutropenia is in order.

The definition of neutropenia in infants is different from that in adults. In infants aged 2 weeks to 1 year, the lower limit of the normal neutrophil count is 1000/µL. After the first year of life, the lower limit is 1500/µL, as in adults.

The mean age at diagnosis of autoimmune neutropenia is 6-12 months, with a range of 3-30 months. Spontaneous recovery occurs by age 5 years, and the mean duration of neutropenia is approximately 20 months.

Go to Neutropenia for complete information on this topic.

Primary and secondary autoimmune neutropenia

Autoimmune neutropenia is either primary or secondary. In primary autoimmune neutropenia, neutropenia is the only abnormality. Infections associated with the primary form are usually limited and mild. [2]

In secondary autoimmune neutropenia, other primary pathologies occur, including systemic autoimmune disease, infections, and malignancy. Autoimmune neutropenia that occurs in the older pediatric age group and adolescents must be regarded as a totally distinct entity separate from chronic benign neutropenia (AIN). The clinical course of the secondary autoimmune neutropenia is not benign. In infants, secondary autoimmune neutropenia is extremely rare.

A case of secondary autoimmune neutropenia. This p A case of secondary autoimmune neutropenia. This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.

Older children, adolescents, and young adults predominantly develop secondary autoimmune neutropenia, and autoimmune hemolytic anemia or immune thrombocytopenia often occur later or at the same time. Antiphospholipid antibody syndrome is common, and ultimately, systemic lupus, Felty syndrome, Sjögren syndrome, and/or a lupuslike illness predominate. Therefore, in this age group, a rigorous search for evidence of other autoimmune phenomena should be made.

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Etiology

Lalezari and colleagues demonstrated neutrophil antibodies in 119 of 121 infants and children with chronic neutropenia, thereby establishing the autoimmune nature of the disease. [3] In the study, all patients had at one time an absolute neutrophil count of less than 500/µL (see the Absolute Neutrophil Count calculator).

AIN is similar to immune thrombocytopenic purpura (ITP) of young children, a more common cytopenia in children. ITP is believed to be triggered by a viral infection and, in some individuals, by immunization. Whether autoimmune neutropenia is commonly triggered by similar etiologies is not known. A similar age group is affected, and recovery is expected in both. Some studies have shown an association with parvovirus B19 infection. Recently, Nakamura et al showed deficiencies in regulatory T cell (CD4+, CD25+) in children with autoimmune neutropenia. [4] Thus, it may be a phenomenon of physiologically delayed maturation of immune regulation.

When identified in AIN, antibodies most commonly include immunoglobulin G (IgG) antibodies against neutrophil glycosylated isoforms of FC gamma RIIIb (or CD 16b) and human neutrophil antigen 1 (HNA1) and, less commonly, against HNA4, which are linked to the plasma membrane via a glycosylphosphatidylinositol anchor.

The human neutrophil antigen (HNA) system consists of HNA-1 through HNA-5. Of these, most common antibodies are directed against HNA-1, which consists of NA-1, NA-2, and SH. They are not anti–human leukocyte antigen (HLA) antibodies. Anti-HLA antibodies may be present, but it is very rarely the cause of AIN.

Bruin et al demonstrated that in patients with AIN, antibodies were exclusively directed against the NA alloantigens, whereas in patients with secondary autoimmune neutropenia, antibodies had pan-FC gamma RIIIb specificity. [5] though other researchers have shown that at the outset of AIN, antibodies against FCγRIIIb may be present (see below).

Bone marrow examination findings are variable and not diagnostic. Bone marrow may be normal, show late-stage maturation arrest, be hyperplastic, or be hypoplastic. In rare cases, granulocyte phagocytosis has been reported. [6]

In a study by Perdikogianni et al, circulating granulocyte colony-stimulating factor (G-CSF) levels (serum or plasma) were found to be normal, even during the neutropenic period, except when patients had infections. [7] On the other hand, Kobayashi et al found that the patient’s sera contained mildly but significantly elevated concentration of G-CSF compared with the control sera. [8]

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Epidemiology

The incidence of autoimmune neutropenia does not vary among different ethnic populations.

A Scottish study estimated that in the Scottish population, the incidence of autoimmune neutropenia is 1 in 100,000 children per year. [9] This may have been an underestimate, however, because laboratory tests are not usually performed in most cases of autoimmune neutropenia.

Autoimmune neutropenia has a slight preponderance in girls in one study, [3] but not in others. [10] The mean age at diagnosis of autoimmune neutropenia is 6-12 months, with a range of 3-30 months.

A high frequency of benign neutropenia is widely recognized in African Americans, Yemenite and Falasha Jews, Black Beduin, blacks of South African extraction, Ethiopians, West Indians, Arab Jordanians, and various tribal groups inhabiting the United Arab Emirates. [11] The gene responsible for this ethnic neutropenia is now identified to be DARC (Duffy antigen/receptor chemokine gene), although the exact mechanism that causes neutropenia is still to be elucidated. [12, 13] In the age group (6 months to 3 years) when autoimmune neutropenia is common, it may be impossible to distinguish these 2 entities in a given child.

Morbidity

Infections associated with AIN, which, as previously mentioned, are usually limited and mild, include just fever, otitis media, upper respiratory tract infection, common colds, viral gastroenteritis, skin infection, stomatitis, and gingivitis. Sepsis and pneumonia are rare. Hajishengallis et al reported on the development of AIN-related periodontal disease in a child aged 2 years. [14] In a study done at St Jude Children’s Research Hospital on children with all types of chronic neutropenia, otolaryngological infections predominated, consisting of recurrent otitis media (81%), viral upper respiratory tract infection (67%), oral ulcers or gingivitis (53%), tonsillitis (39%), and sinusitis (37%). [15]

A case of secondary autoimmune neutropenia. This p A case of secondary autoimmune neutropenia. This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.

This is in contrast to severe, life-threatening infections (quite often systemic) experienced by infants with severe congenital neutropenia (Kostmann disease and other types), children with aplastic anemia, or children with neutropenia who are receiving chemotherapy.

The reasons for this difference between primary autoimmune and severe congenital neutropenia may be related to the fact that individuals with autoimmune neutropenia have an adequate bone marrow neutrophil reserve and can therefore mount some level of neutrophil response to an infection, even though these neutrophils are rapidly destroyed; this is in contrast to patients with poor or no bone marrow reserve.

In a study of infections in 73 children with neutropenia, Fioredda et al reported a rate of 0.66 infections per patient with AIN (compared with 5.75 infections per patient with severe congenital neutropenia). [16] This figure for AIN may be an overestimate, however, since may have been a selection bias, in that the neutropenia registry used in the study contained more severly affected AIN patients.

Although febrile illnesses appear to be more common in children with AIN than in healthy children, AIN usually does not affect the child's growth and development, although some exceptions occur. (See History.)

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Prognosis

The prognosis is excellent. The condition usually lasts only 2-3 years before spontaneous resolution, and virtually all patients recover by age 5 years.

Spontaneous recovery after 6-24 months is typical. If it persists beyond age 4-5 years, consider other diagnoses. It is important to follow these patients into recovery for this reason.

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Patient Education

Thoroughly discussing the natural history with the patient’s parents and/or caregivers is important, since this can prevent undue anxiety created by low neutrophil counts.

In addition, because medical advice is usually sought after infections have occurred in a child with autoimmune neutropenia, discussing the condition’s natural history validates the experience of the parents and/or caregivers and, in turn, increases their confidence in the physician's diagnosis and treatment.

It is important for patients to maintain good dental hygiene in order to prevent gingivitis, stomatitis, and other mucous membrane infections of the mouth.

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